165 research outputs found
Variazioni sul tema della prigionia: La Captive di Chantal Akerman.
Properties of the hole-doped Ln1−xAxMnO3 (Ln=rare earth, A=alkaline earth, x<0.5) are compared with those of the electron-doped compositions (x>0.5). Charge ordering is the dominant interaction in the latter class of manganates unlike ferromagnetism and metallicity in the hole-doped materials. Properties of charge-ordered (CO) compositions in the hole- and electron-doped regimes, Pr0.64Ca0.36MnO3 and Pr0.36Ca0.64MnO3, differ markedly. Thus, the CO state in the hole-doped Pr0.64Ca0.36MnO3 is destroyed by magnetic fields and by substitution of Cr3+ or Ru4+ (3%) in the Mn site, while the CO state in the electron-doped Pr0.36Ca0.64MnO3 is essentially unaffected. It is not possible to induce long-range ferromagnetism in the electron-doped manganates by increasing the Mn-O-Mn angles up to 165 and 180° as in La0.33Ca0.33Sr0.34MnO3; application of magnetic fields and Cr/Ru substitution (3%) do not result in long-range ferromagnetism and metallicity. Application of magnetic fields on the Cr/Ru-doped, electron-doped manganates also fails to induce metallicity. These unusual features of the electron-doped manganates suggest that the electronic structure of these materials is likely to be entirely different from that of the hole-doped ones, as verified by first-principles linearized muffin-tin orbital calculations
Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection
With over 3.5 billion people at risk and approximately 390 million human infections per year, dengue virus (DENV) disease strains health care resources worldwide. Previously, we and others established models for DENV pathogenesis in mice that completely lack subunits of the receptors (Ifnar and Ifngr) for type I and type II interferon (IFN) signaling; however, the utility of these models is limited by the pleotropic effect of these cytokines on innate and adaptive immune system development and function. Here, we demonstrate that the specific deletion of Ifnar expression on subsets of murine myeloid cells (LysM Cre(+) Ifnar(flox/flox) [denoted as Ifnar(f/f) herein]) resulted in enhanced DENV replication in vivo. The administration of subneutralizing amounts of cross-reactive anti-DENV monoclonal antibodies to LysM Cre(+) Ifnar(f/f) mice prior to infection with DENV serotype 2 or 3 resulted in antibody-dependent enhancement (ADE) of infection with many of the characteristics associated with severe DENV disease in humans, including plasma leakage, hypercytokinemia, liver injury, hemoconcentration, and thrombocytopenia. Notably, the pathogenesis of severe DENV-2 or DENV-3 infection in LysM Cre(+) Ifnar(f/f) mice was blocked by pre- or postexposure administration of a bispecific dual-affinity retargeting molecule (DART) or an optimized RIG-I receptor agonist that stimulates innate immune responses. Our findings establish a more immunocompetent animal model of ADE of infection with multiple DENV serotypes in which disease is inhibited by treatment with broad-spectrum antibody derivatives or innate immune stimulatory agents
Geometrical Effect in 2D Nanopores
A long-standing problem in the application of solid-state nanopores is the lack of the precise control over the geometry of artificially formed pores compared to the well-defined geometry in their biological counterpart, that is, protein nanopores. To date, experimentally investigated solid-state nanopores have been shown to adopt an approximately circular shape. In this Letter, we investigate the geometrical effect of the nanopore shape on ionic blockage induced by DNA translocation using triangular h-BN nanopores and approximately circular molybdenum disulfide (MoS2) nanopores. We observe a striking geometry-dependent ion scattering effect, which is further corroborated by a modified ionic blockage model. The well-acknowledged ionic blockage model is derived from uniform ion permeability through the 2D nanopore plane and hemisphere like access region in the nanopore vicinity. On the basis of our experimental results, we propose a modified ionic blockage model, which is highly related to the ionic profile caused by geometrical variations. Our findings shed light on the rational design of 2D nanopores and should be applicable to arbitrary nanopore shapes.This work was financially supported by the European Research Council (grant 259398, PorABEL), by a Swiss National Science Foundation (SNSF) Consolidator grant (BIONIC BSCGI0_157802), by SNSF Sinergia grant 147607 ... The work performed in Cambridge was supported by the EPSRC Cambridge NanoDTC, EP/L015978/1. The work performed in UIUC was supported by grants from Oxford Nanopore Technology and the Seeding Novel Interdisciplinary Research Program of the Beckman Institute. The UIUC authors gratefully acknowledge also supercomputer time provided through the Extreme Science and Engineering Discovery Environment (XSEDE) grant MCA93S028 and by the University of Illinois at Urbana-Champaign on the TAUB cluster
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Genetic mechanisms of critical illness in COVID-19.
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.
Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability
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